U.S. patent application number 10/501678 was filed with the patent office on 2006-07-27 for pharmaceutical composition and method for treating disorders of the central nervous system.
Invention is credited to BradleyS Galer, ThomasG Schlagheck.
Application Number | 20060167032 10/501678 |
Document ID | / |
Family ID | 27613313 |
Filed Date | 2006-07-27 |
United States Patent
Application |
20060167032 |
Kind Code |
A1 |
Galer; BradleyS ; et
al. |
July 27, 2006 |
Pharmaceutical composition and method for treating disorders of the
central nervous system
Abstract
Disorders of the ventral nervous system (CNS) are treated by the
administration of a GABA analog such as gabapentin or pregablin, an
NMDA receptor antagonist such as dextromethorphan or d-methodone
and, optionally, another pharmacologically active substance, e.g.,
one which is effective for the treatment of a CNS disorder.
Inventors: |
Galer; BradleyS; (West
Chester, PA) ; Schlagheck; ThomasG; (Naples,
FL) |
Correspondence
Address: |
DILWORTH & BARRESE, LLP
333 EARLE OVINGTON BLVD.
UNIONDALE
NY
11553
US
|
Family ID: |
27613313 |
Appl. No.: |
10/501678 |
Filed: |
January 10, 2003 |
PCT Filed: |
January 10, 2003 |
PCT NO: |
PCT/US03/00794 |
371 Date: |
July 12, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60349773 |
Jan 16, 2002 |
|
|
|
Current U.S.
Class: |
514/282 ;
514/551; 514/561; 514/617; 514/663 |
Current CPC
Class: |
A61K 31/195 20130101;
A61P 25/06 20180101; A61P 25/00 20180101; A61P 25/08 20180101; A61P
25/22 20180101; A61P 25/14 20180101; A61P 25/18 20180101; A61K
2300/00 20130101; A61P 25/28 20180101; A61P 43/00 20180101; A61K
2300/00 20130101; A61K 31/195 20130101; A61K 31/44 20130101; A61P
25/24 20180101; A61K 31/44 20130101 |
Class at
Publication: |
514/282 ;
514/561; 514/551; 514/663; 514/617 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 31/22 20060101 A61K031/22; A61K 31/195 20060101
A61K031/195; A61K 31/13 20060101 A61K031/13; A61K 31/165 20060101
A61K031/165 |
Claims
1. A pharmaceutical composition comprising: (a) at least one GABA
analog and (b) at least one nontoxic antagonist for the NMDA
receptor, the combined amount of (a) and (b) in the composition
being a CNS disorder-treating amount and the amount of (b) in the
composition being sufficient to potentiate the CNS
disorder-treating effectiveness of (a).
2. The composition of claim 1 wherein the GABA analog possesses the
structure ##STR3## wherein R.sub.1 is hydrogen or lower alkyl and n
is an integer of from 4 to 6, and the pharmaceutically acceptable
salts thereof.
3. The composition of claim 1 wherein the GABA analog is
gabapentin.
4. The composition of claim 1 wherein the GABA analog possesses the
structure ##STR4## wherein R.sub.1 is a straight or branched alkyl
of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6
atoms, R.sub.2 is hydrogen or methyl and R.sub.3 is hydrogen,
methyl, or carboxyl, and the pharmaceutically acceptable salts,
diasteromers and enantiomers thereof.
5. The composition of claim 1 wherein the GABA analog is
pregabalin.
6. The composition of claim 1 wherein the nontoxic NMDA receptor
antagonist is at least one member selected from the group
consisting of dextromethorphan, dextrorphan, amantadine, memantine,
d-methadone and pharmaceutically acceptable salts thereof.
7-10. (canceled)
11. The composition of claim 1 wherein (a) and (b) of the
pharmaceutical composition is present in a combined sustained
release carrier.
12. The composition of claim 1 wherein (a) and (b) of the
pharmaceutical composition are present in separate sustained
release carriers.
13. The composition of claim 1 wherein the pharmaceutical
composition contains a therapeutically effective amount of at least
one other pharmacologically active substance (c).
14. The composition of claim 1 wherein the pharmaceutical
composition contains a therapeutically effective amount of at least
one other pharmacologically active substance (c) which is a drug
for treating a CNS disorder.
15. The composition of claim 1 wherein the pharmaceutical
composition contains a therapeutically effective amount of at least
one other pharmaceutically active substance (c) which is a drug or
drug combination for the treatment of a CNS disorder selected from
the group consisting of nicotine, nicotinic compounds, tacrine,
donezepil, carbidopa in combination with levodopa, selegiline,
bromocriptine, haloperidol, clonidine, pimozide, fluphenazine,
benzodiazepines, clonazepam, clorpromazine, fluoxetine,
clomipramine, amitriptyline, nortriptyline, imipramine, buspirone,
bupropion hydrochloride, venlafaxine, milnacipran, duloxetine,
mirtazapine, nefazodone, paroxetine, sertraline, riluzole,
trazodone, doxepin and methylphenidate.
16. The composition of claim 1 wherein the CNS disorder is
classified in the International Classification of Diseases of the
World Health Organization.
17. The composition of claim 1 wherein the CNS disorder is
presenile dementia, senile dementia, movement disorder,
hyperkinesias, mania, attention deficit disorder, depression,
anxiety, obsessive-compulsive disorder, dyslexia, schizophrenia,
headache disorder, epilepsy, Tourette's syndrome or Asperger's
syndrome.
18-31. (canceled)
32. A pharmaceutical composition comprising: (a) at least one GABA
analog in an extended release form in combination with (b) at least
one nontoxic antagonist for the NMDA receptor in an immediate
release form, the combined amount of (a) and (b) in the composition
being a CNS disorder-treating amount and the amount of (b) in the
composition being sufficient to potentiate the CNS
disorder-treating effectiveness of (a).
33. The composition of claim 32 wherein the GABA analog possesses
the structure ##STR5## wherein R.sub.1 is hydrogen or lower alkyl
and n is an integer of from 4 to 6, and the pharmaceutically
acceptable salts thereof.
34. The composition of claim 32 wherein the GABA analog is
gabapentin.
35. The composition of claim 32 wherein the GABA analog possesses
the structure ##STR6## wherein R.sub.1 is a straight or branched
alkyl of from 1 to 6 carbon atoms, phenyl, or cycloaklyl of from 3
to 6 carbon atoms, R.sub.2 is hydrogen or methyl and R.sub.3 is
hydrogen, methyl, or carboxyl, and the pharmaceutically acceptable
salts, diastereomers and enantiomers thereof.
36. The composition of claim 32 wherein the GABA analog is
pregabalin.
37. The composition of claim 32 wherein the nontoxic NMDA receptor
antagonist is at least one member selected from the group
consisting of dextromethorphan, dextrorphan, amantadine, memantine,
d-methadone and pharmaceutically acceptable salts thereof.
38-41. (canceled)
42. The composition of claim 32 wherein the at least one nontoxic
NMDA receptor antagonist is present in an immediate release
carrier.
43. The composition of claim 32 wherein the extended release form
is an extended release carrier comprising abase material selected
from the group consisting of a hydrophilic polymer, a hydrophobic
polymer, a long chain hydrocarbon, a polyalkylene glycol, higher
aliphatic alcohols, acrylic resins, and mixtures thereof.
44. The composition of claim 43 wherein the at least one nontoxic
NMDA receptor antagonist is applied to the extended release
carrier's exterior surface.
45. The composition of claim 32 wherein the extended release form
comprises a base material having a coating that controls the
release of the GABA analog.
46. The composition of claim 45 wherein the coating includes the at
least one nontoxic NMDA receptor antagonist.
47. The composition of claim 32 wherein the pharmaceutical
composition contains a therapeutically effective amount of (c) at
least one other pharmacologically active substance.
48. The composition of claim 47 wherein the pharmacologically
active substance (c) is included in the extended release form.
49. The composition of claim 47 wherein the pharmacologically
active substance (c) is included in the immediate release form.
50. The composition of claim 47 wherein the pharmacologically
active substance (c) is included in both the extended release form
and the immediate release form.
51. The composition of claim 32 wherein the pharmaceutical
composition contains a therapeutically effective amount of at least
one other pharmacologically active substance (c) which is a drug
for treating a CNS disorder.
52. The composition of claim 32 wherein the pharmaceutical
composition contains a therapeutically effective amount of at least
one other pharmaceutically active substance (c) which is a drug or
drug combination for the treatment of a CNS disorder selected from
the group consisting of nicotine, nicotinic compounds, tacrine,
donezepil, carbidopa in combination with levodopa, selegiline,
bromocriptine, haloperidol, clonidine, pimozide, fluphenazine,
benzodiazepines, clonazepam, clorpromazine, fluoxetine,
clomipramine, amitriptyline, nortriptyline, imipramine, buspirone,
bupropion hydrochloride, venlafaxine, milnacipran, duloxetine,
mirtazapine, nefazodone, paroxetine, sertraline, riluzole,
trazodone, doxepin and methylphenidate.
53. The composition of claim 32 wherein the CNS disorder is
classified in the International Classification of Diseases of the
World Health Organization.
54. The composition of claim 32 wherein the CNS disorder is
presenile dementia, senile dementia, movement disorder,
hyperkinesias, mania, attention deficit disorder, depression,
anxiety, obsessive-compulsive disorder, dyslexia, schizophrenia,
headache disorder, epilepsy, Tourette's syndrome or Asperger's
syndrome.
55. A method of treating a CNS disorder which comprises
administering to a mammal in need of treatment for a CNS disorder A
CNS disorder treating amount of pharmaceutical composition
comprising: (a) at least one GABA analog and (b) at least one
nontoxic antagonist for the NMDA receptor, the combined amount of
(a) and (b) in the composition being a CNS disorder-treating amount
and the amount of (b) in the composition being sufficient to
potentiate the CNS disorder-treating effectiveness of (a).
56. A method of treating a CNS disorder which comprises
administering to a mammal in need of treatment for a CNS disorder A
CNS disorder treating amount of pharmaceutical composition
comprising: (a) at least one GABA analog in an extended release
form in combination with (b) at least one nontoxic antagonist for
the NMDA receptor in an immediate release form, the combined amount
of (a) and (b) in the composition being a CNS disorder-treating
amount and the amount of (b) in the composition being sufficient to
potentiate the CNS disorder-treating effectiveness of (a).
Description
BACKGROUND
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of earlier filed and copending U.S. Provisional Application
No. 60/349,773, filed Jan. 16, 2002, the contents of which are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] This invention relates to a pharmaceutical composition for
treating disorders of the central nervous system (CNS).
[0004] 2. Background of Related Art
[0005] CNS disorders are types of neurological disorders. CNS
disorders can be drug induced; can be attributed to genetic
predisposition, infection or trauma; or can be of unknown etiology.
CNS disorders comprise neuropsychiatric disorders, neurological
diseases and mental illnesses, and include neurodegenerative
diseases, behavioral disorders, cognitive disorders and cognitive
affective disorders. There are several CNS disorders whose clinical
manifestations have been attributed to CNS dysfunction, i.e.,
disorders resulting from inappropriate levels of neurotransmitter
release, inappropriate properties of neurotransmitter receptors,
and/or inappropriate interaction between neurotransmitters and
neurotransmitter receptors. Several CNS disorders can be attributed
to a cholinergic deficiency, a dopaminergic deficiency, an
adrenergic deficiency and/or a serotonergic deficiency. CNS
disorders of relatively common occurrence include presenile
dementia (early onset Alzheimer's disease), senile dementia
(dementia of the Alzheimer's type), movement disorders associated
with Parkinsonism including Parlinson's disease, Restless Leg
Syndrome (RLS), Lewy Body Disease (LBD), supranuclear palsy (SNP),
Huntington's chorea, tardive dyskinesia, hyperlinesia, mania,
attention deficit disorder, depression, anxiety,
obsessive-compulsive disorders, dyslexia, schizophrenia, headache
disorders such as migraine and cluster headaches, epilepsy and
Tourette's syndrome.
[0006] GABA analogs are known in the art and include those
disclosed, e.g., in U.S. Pat. Nos. 4,024,175, 4,087,544 and
5,563,175, the contents of each of which are incorporated by
reference herein.
[0007] N-methyl-D-aspartate (NMDA) receptor antagonists are well
known in the art and encompass, for example, dextromethorphan,
dextrorphan, memantine, amantidine, d-methadone and their
pharmaceutically acceptable salts. NMDA receptor antagonists are
known to inhibit the development of tolerance to and/or dependence
on addictive drugs, e.g., narcotic analgesics such as morphine,
codeine, etc., as disclosed in U.S. Pat. Nos. 5,321,012 and
5,556,838, and to treat chronic pain as disclosed in U.S. Pat. No.
5,502,058, the contents of each of which are incorporated by
reference herein.
[0008] Nontoxic NMDA receptor antagonists, such as
dextromethorphan, are also known to enhance the effects of some
drugs, especially opioid analgesics. See, e.g., U.S. Pat. Nos.
5,502,058 and 5,840,731, respectively, the contents of which are
incorporated by reference herein. In some cases, the nontoxic NMDA
receptor antagonist is administered in combination with a local
anesthetic. See U.S. Pat. No. 5,352,683, the contents of which are
incorporated by reference herein.
[0009] It is an object of the present invention to provide a CNS
disorder-treating composition and method in which the CNS
disorder-treating activity of a GABA analog is potentiated by a
nontoxic NMDA receptor antagonist.
[0010] It is another object of the present invention to provide a
CNS disorder-treating single unit dosage form containing a GABA
analog, at least one nontoxic NMDA receptor antagonist and,
optionally, one or more additional pharmacologically active
substances, e.g., another drug which is effectual for treatment of
a CNS disorder.
SUMMARY OF THE INVENTION
[0011] By way of meeting the foregoing as well as other objects of
the invention, a method of treating a CNS disorder is provided
which comprises administering to a mammal in need of treatment for
a CNS disorder a pharmaceutical composition which comprises (a) at
least one GABA analog and (b) at least one nontoxic antagonist, or
blocker, for the N-methyl-D-aspartate (NMDA) receptor, the combined
amount of (a) and (b) in the composition being a CNS
disorder-treating amount and the amount of (b) in the composition
being sufficient to potentiate the CNS disorder-treating
effectiveness of (a). Optionally, the pharmaceutical composition
utilized in the methods of the present invention may include a
third component, (c), which is a therapeutically effective amount
of at least one other CNS disorder-treating drug or other
pharmacologically active substance.
[0012] The expression "NMDA receptor antagonist" shall be
understood herein to be synonymous with, and to include, the
expressions "antagonist for the NMDA receptor" and "blocker for the
NMDA receptor", and shall be understood to include all nontoxic
substances that block an NMDA receptor binding site.
[0013] The term "nontoxic" as used herein shall be understood in a
relative sense and is intended to designate any substance that has
been approved by the United States Food and Drug Administration
("FDA") for administration to humans or, in keeping with
established regulatory criteria and practice, is susceptible to
approval by the FDA for administration to humans. The term
"nontoxic" is also used herein to distinguish the NMDA receptor
antagonists that are useful in the practice of the present
invention from NMDA receptor antagonists such as MK 801 (the
compound
5-methyl-10,11-dihydro-SH-dibenze[a,d]cyclohepten-5,10-imine), CPP
(the compound 3-[2-carboxypiperazin-4-yl]propyl-1-phosphonic acid)
and PCP (the compound 1-(1-phenylcyclohexyl) piperidine) whose
toxicities effectively preclude their therapeutic use.
[0014] The expression "CNS disorder-treating" shall be understood
herein to be synonomous with, and to include, the expressions "CNS
disorder-alleviating", "CNS disorder-suppressing" and "CNS
disorder-inhibiting", as the CNS disorder-treating method of the
invention is applicable to the alleviation of an existing CNS
disorder as well as the suppression or inhibition of a CNS disorder
in a subject known to manifest such a disorder.
[0015] The term "potentiate", as applied to the pharmaceutical
composition and CNS disorder-treating method of the invention,
shall mean that the presence of the nontoxic NMDA receptor
antagonist in the CNS disorder-treating composition does one of the
following: (i) increases CNS disorder-treating effects so that the
CNS disorder-treating effects from the composition of the present
invention is greater than the sum of the CNS disorder-treating
effects attributable to its GABA analog and nontoxic NMDA receptor
antagonist components when each of these components is administered
alone, (ii) provides the same level of CNS disorder-treating
effects using a lower amount of GABA analog compared to the GABA
analog alone, (iii) creates a synergistic effect when administered
with the GABA analog so that CNS disorder-treating effects are
obtained when the CNS disorder-treating composition of the present
invention is administered, but would not be obtained if the
nontoxic NMDA receptor antagonist and GABA analog were administered
alone and to the exclusion of the other; (iv) suppresses or
minimizes any adverse effects of the GABA analog.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The present invention is useful for treating many CNS
disorders, including those mentioned above. Some of the CNS
disorders treatable by a pharmaceutical composition in accordance
with this invention as classified in the International
Classification of Diseases of the World Health Organization are as
follows:
Dementia in Alzheimer's Disease
[0017] F01 Vascular dementia [0018] F02 Dementia in other diseases
classified elsewhere [0019] F05 Delirium, not induced by alcohol
and other psychoactive substances [0020] F06 Other mental disorders
due to brain damage and dysfunction and to physical disease [0021]
F06.0 Organic hallucinosis [0022] F06.2 Organic delusional
[schizophrenia-like] disorder [0023] F06.3 Organic mood [affective]
disorder [0024] F06.4 Organic anxiety disorder [0025] F06.7 Mild
cognitive disorder [0026] F07.1 Postencephalitic syndrome [0027]
F07.2 Postconcussional syndrome [0028] F11. Mental and behavioural
disorders due to use of opioids [0029] F12. Mental and behavioural
disorders due to use of cannabinoids [0030] F13. Mental and
behavioural disorders due to use of sedatives or hypnotics [0031]
F14. Mental and behavioural disorders due to use of cocaine [0032]
F16. Mental and behavioural disorders due to use of hallucinogens
[0033] F17. Mental and behavioural disorders due to use of tobacco
Schizophrenia Manic Episode [0034] F30.0 Hypomania [0035] F30.1
Mania without psychotic symptoms [0036] F30.2 Mania with psychotic
symptoms [0037] F30.8 Other manic episodes [0038] F30.9 Manic
episode, unspecified [0039] F31 Bipolar affective disorder [0040]
F31.0 Bipolar affective disorder, current episode hypomanic [0041]
F31.1 Bipolar affective disorder, current episode manic without
psychotic symptoms [0042] F31.2 Bipolar affective disorder, current
episode manic with psychotic symptoms [0043] F31.3 Bipolar
affective disorder, current episode mild or moderate depression
[0044] F31.4 Bipolar affective disorder, current episode severe
depression without psychotic symptoms [0045] F31.5 Bipolar
affective disorder, current episode severe depression with
psychotic symptoms [0046] F32 Depressive episode [0047] F34
Persistent mood [affective] disorders [0048] F34.0 Cyclothymia
[0049] F34.1 Dysthymia [0050] F41 Other anxiety disorders [0051]
F41.0 Panic disorder [episodic paroxysmal anxiety] [0052] F41.1
Generalized anxiety disorder [0053] F41.2 Mixed anxiety and
depressive disorder [0054] F41.3 Other mixed anxiety disorders
[0055] F41.8 Other specified anxiety disorders [0056] F41.9 Anxiety
disorder, unspecified [0057] F42 Obsessive-compulsive disorder
[0058] F43.1 Post-traumatic stress disorder [0059] F43.2 Adjustment
disorders [0060] F51 Nonorganic sleep disorders [0061] F55 Abuse of
non-dependence-producing substances [0062] F55.0 Antidepressants
[0063] F55.2 Analgesics [0064] F61 Mixed and other personality
disorders [0065] F63 Habit and impulse disorders Diseases of the
Nervous System (G00-G99) Seasonal Affective Disorder
[0066] Additional CNS disorders that are treatable in accordance
with the invention include:
AIDS--Neurological Manifestations
Acquired Epileptiform Aphasia
Amyotrophic Lateral Sclerosis
Anoxia or Hypoxia
Apraxia
Attention Deficit-Hyperactivity Disorder
Autism
Brain Injury
Cerebral Palsy
Chorea
Dementia with Lewy Bodies
Encephalitis and Meningitis
Encephaloceles
Epilepsy
Head Injury
Herpes Zoster
Hypoxia
Immune-Mediated Encephalomyelitis
Kuru
Lennox-Gastaut Syndrome
Leukodystrophy
Lewy Body Dementia
Lissencephaly
Locked-In Syndrome
Lou Gehrig's Disease
Lupus--Neurological Sequelae
Lyme Disease--Neurological Sequelae
Meningitis
Motor Neuron Diseases
Moyamoya Disease
Multiple System Atrophy with Postural Hypotension
Narcolepsy
Neurofibromatosis
Neurological Manifestations of AIDS
Neurological Sequelae Of Lupus
Neurological Sequelae Of Lyme Disease
Niemann-Pick Disease
Parkinson's Disease
Pick's Disease
Post-Polio Syndrome
Postinfectious Encephalomyelitis
Progressive Supranuclear Palsy
Pseudotumor Cerebri
Restless Legs Syndrome
Schilder's Disease
Sydenham Chorea
Syncope
Systemic Lupus Erythematosus
Tardive Dyskinesia
Tremor
Wilson's Disease
[0067] In addition to the foregoing CNS disorders, other CNS
disorders, or neurological diseases, that may be usefully treated
by the pharmaceutical composition of this invention include, but
are not limited to, Tourette's syndrome, Asperger's syndrome, and
similar genetic and infectious diseases affecting the brain and/or
spinal cord.
[0068] Useful GABA analogs include those disclosed, e.g., in U.S.
Pat. Nos. 4,024,175, 4,087,544 and 5,563,175. A preferred
embodiment of the therapeutic composition herein utilizes a GABA
analog of Formula I ##STR1## wherein R.sub.1 is hydrogen or lower
alkyl and n is an integer of from 4 to 6, and the pharmaceutically
acceptable salts thereof.
[0069] A preferred GABA analog of Formula I wherein R.sub.1 is
hydrogen and n is 5 is the compound 1-(aminomethyl)-cyclohexane
acetic acid, known generically as gabapentin. Other preferred GABA
analogs of Formula I wherein the cyclic ring is substituted, for
example, with alkyl such as methyl or ethyl, include such compounds
as (1-aminomethyl-3-methylcyclohexyl)acetic acid,
(1-aminomethyl-3-methylcyclopentyl) acetic acid, and
(1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid.
[0070] Another preferred embodiment of the therapeutic composition
herein utilizes a GABA analog of Formula II ##STR2## wherein
R.sub.1 is a straight or branched alkyl of from 1 to 6 carbon
atoms, phenyl, or cycloaklyl of from 3 to 6 carbon atoms, R.sub.2
is hydrogen or methyl and R.sub.3 is hydrogen, methyl, or carboxyl,
and the pharmaceutically acceptable salts, diastereomers and
enantiomers thereof.
[0071] Preferred GABA analogs of Formula II are those wherein
R.sub.2 and R.sub.3 are both hydrogen and R.sub.1 is
--(CH.sub.2).sub.0-2-iC.sub.4H.sub.9 as an (R), (S), or (R,S)
isomer. A preferred compound of this type is
3-aminomethyl-5-methyl-hexanoic acid, and especially
(S)-3-(aminomethyl)-5-methylhexanoic acid, known generically as
pregabalin, Pregabalin is also known as "CI-1008" and
"S-(+)-3-IBG." Another preferred compound of Formula II is
3-(1-aminoethyl)-5-methylheptanoic acid.
[0072] GABA analogs, including those described above, are readily
available, either commercially or by synthetic methodology
well-known to those skilled in the art of organic chemistry.
[0073] Among the nontoxic substances that block the NMDA receptor
and as such are useful for potentiating the CNS disorder-treating
activity of the GABA analog in accordance with this invention are
dextromethorphan ((+)-3-hydroxy-N-methylmorphinan), its metabolite
dextrorphan ((+)-3-hydroxy-N-methylmorphinan), amantadine (1-amino
adamantine), memantine (3,5 dimethylaminoadamantone), d-methadone
(d-form of 6-dimethylamino-4,4-diphenyl-3-heptanone hydrochloride),
their mixtures and their pharmaceutically acceptable salts.
[0074] Of the foregoing NMDA-receptor antagonists, dextromethorphan
is preferred due to its wide use in over-the-counter medications
where it functions as a cough suppressant.
[0075] For purposes of this disclosure, "extended release" includes
"controlled release" and "sustained release" and pertains to the
release of pharmaceutical agents at a defined level over an
extended period of time.
[0076] The expression "dosage form" is understood to include "unit
dosage form". The expression "unit dosage form" means a physically
discrete unit which contains specified amounts of a GABA analog in
combination with the nontoxic NMDA receptor antagonist, and any
other pharmacologically active substance or pharmaceutical
excipient, which amounts are selected so that a fixed number, e.g.
one, of the units is suitable to achieve a desired therapeutic
effect.
[0077] In the pharmaceutical composition of this invention, the
combined amount of GABA analog and nontoxic NMDA receptor
antagonist must be a CNS disorder-treating amount, the amount of
NMDA receptor antagonist in the composition being sufficient to
potentiate the CNS disorder-treating activity of the GABA analog
component of the composition. The GABA analog can be present in the
pharmaceutical composition in an amount which, if administered by
itself, would constitute a CNS disorder-treating amount or it can
be present in the composition in less than this amount provided
that the amount of nontoxic NMDA receptor antagonist present
therein is sufficient to provide an effective CNS disorder-treating
dose.
[0078] As noted above, the nontoxic NMDA receptor antagonist must
be present in the pharmaceutical composition in an amount
sufficient to potentiate the CNS disorder-treating activity of the
GABA analog. It would be recognized by one skilled in the art that
this amount will relate to the amount of the GABA analog present
and its CNS disorder-treating capacity, the nature of the nontoxic
NMDA receptor antagonist and its ability to enhance the CNS
disorder-treating effect, as well as the particular formulation
containing the active substances. As those skilled in the art will
recognize, many factors that modify the action of the active
substances herein, such as the state and circumstances of the host
being treated, will be taken into account by the treating physician
and include, for example, the age, body weight, sex, diet and
condition of the subject, including metabolic status, the time of
administration, the rate and route of administration, and so forth.
Optimal dosages for a given set of conditions can be ascertained by
those skilled in the art using conventional dosage determination
tests.
[0079] A useful intravenous combined dosage form can, e.g., contain
from about 5 to about 50 mg of the selected GABA analog and a
useful oral dosage form can contain form about 10 to about 800 mg
of the GABA analog. Given these wide variations in dosage levels of
the GABA analog component, there can similarly be a wide variation
in the dosage level of the nontoxic NMDA receptor antagonist. For
the preferred nontoxic NMDA receptor antagonist, dextromethorphan
in the form of its hydrobromide salt, dosages can generally range
from about 10 mg to about 750 mg per 70 kg body weight, preferably
from about 30 mg to about 500 mg per 70 kg body weight.
[0080] In addition to the GABA analog and at least one nontoxic
NMDA receptor antagonist, the pharmaceutical composition herein can
optionally contain at least one other pharmacologically active
substance which is useful for the treatment of CNS disorders,
including any of the specific CNS disorders mentioned above.
Illustrative, but not exclusive, of such other pharmaceutically
active substances and the specific CNS disorders for which they are
indicated to be useful are: [0081] Antidepressants, including
trazodone, [0082] Tricyclics, including amitriptyline (Elevil.TM.),
desipramine (Norpramin.TM.), doxepin (Sinequan.TM. or Adapin.TM.),
imipramine (Tofranil.TM.), nortriptyline (Aventyl.TM. or
Pamelor.TM.), clomiprimine (Anafranil.TM.) [0083] selective
serotonin re-uptake inhibitors (SSRIs), including citalopram
(Celexa.TM.), fluoxetine (Prozac.TM.), fluvoxamine (Luvox.TM.),
paroxetine (Paxil.TM.), sertraline (Zoloft.TM.), temazepam
(Restoril.TM.) [0084] Norepinephrine Serotonin Reuptake Inhibitors
("NSRIs"), including venlafaxine (Effexor.TM.), mirtazapine
(Remeron.TM.), nefazodone (Serzone.TM.), milnacipran, and
duloxetine (Cymbalta.RTM.) [0085] buspirone (BuSpar.RTM.) [0086]
bupropion hydrochloride (Wellbutrin.RTM.) [0087] Dopaminergic,
including levodopa and levodopa in combination with carbidopa
[0088] Memory-enhancing or Memory-stabilizing [0089]
acetylcholinesterase (AChE) inhibitors, including tacrine and
donezepil; selegiline [0090] Antipsychotic and/or
Antischizophrenic, including chlorpromazine (Thorazine.TM.),
haloperidol (Haldol.TM.), pimozide, fluphenazine [0091]
Anti-addiction drugs [0092] Opioid antagonists [0093] Dopaminergic
[0094] Nicotinergic, including nicotine and nicotinic compounds
[0095] Riluzole [0096] methylphenidate (Ritalin) [0097]
Parkinsonian drugs [0098] Methyldopa [0099] Anticholinergic [0100]
Dopaminergic, including bromocriptine, [0101] Adrenergic agonists,
including clonidine [0102] Anti-anxiety drugs, including
benzodiazepines and clonazepam
[0103] These and other drugs for treating CNS disorders can be
included in the pharmaceutical composition of this invention at
known and conventional dosage levels. It will also be apparent to
one skilled in the art that many of the drugs noted above can be
classified in more than one category for more than one use. Thus,
for example, clonidine, which was originally marketed for the
treatment of hypertension, has found uses in treating opiate
withdrawal, anxiety, and attention deficit disorder.
[0104] The pharmaceutical composition of this invention will
ordinarily be formulated with one or more pharmaceutically
acceptable ingredients in accordance with known and established
practice. Thus, the pharmaceutical composition can be formulated as
a liquid, powder, elixir, injectable solution, etc. Formulations
for oral use can be provided as tablets or hard capsules wherein
the pharmacologically active ingredients are mixed with an inert
solid diluent such as calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredients
are mixed with an oleaginous medium, e.g., liquid paraffin or olive
oil. Formulations include those of immediate-release preparations
and those providing modified-release or extended release
characteristics, such as those that provide dosing every 6 hours,
every 8 hours, every 12 hours, every 24 hours, up to those that
provide dosing intervals up to a monthly basis.
[0105] While it is within the scope of the invention to
concurrently administer separate dosage forms of GABA analog and
the nontoxic NMDA receptor antagonist to treat a CNS disorder, as a
matter of convenience these drugs are preferably coadministered as
a single, or combined, dosage form. All modes of administration are
contemplated, e.g., orally, rectally, parenterally, intrathecally,
intranasally, transdermally, and topically. The term parenteral as
used herein includes subcutaneous, intravenous, intramuscular and
intrasternal injections or infusion techniques. In addition to the
treatment of warm-blooded animals such as mice, rats, horses,
cattle, sheep, dogs, cats, etc., the compounds of the invention are
effective in the treatment of humans.
[0106] As the pharmaceutical compositions of the present invention
contain at least two components, the pharmaceutical compositions
may provide for the immediate release of the GABA analog and the
NMDA receptor antagonist, the extended release of the two
components by inclusion in the same or different sustained release
carrier(s), or, in some cases, the immediate release of one
component and the extended release of the other component.
Similarly, where at least one other drug for treating a CNS
disorder or a therapeutically effective amount of at least one
other pharmacologically active substance is included in the
pharmaceutical composition in addition to the GABA analog and the
at least one nontoxic NMDA receptor antagonist, the pharmaceutical
composition may provide for the immediate release of the
components, the extended release of the components by inclusion in
the same or different sustained release carrier(s), or the
immediate release of some component(s) and the extended release of
the other component(s).
[0107] Sustained release of the pharmaceutical composition may be
accomplished in accordance with formulations/methods of manufacture
known to those skilled in the art of pharmaceutical formulation,
e.g., via the incorporation of the pharmaceutical composition in an
extended release carrier; or via a controlled release coating of a
carrier containing the pharmaceutical composition.
[0108] In one embodiment, the pharmaceutical composition comprises
a GABA analog in an extended release form in combination with at
least one nontoxic NMDA receptor antagonist in an unmodified state
capable of immediate release. In another embodiment, an extended
release carrier containing the GABA analog is combined with an
immediate release carrier containing the nontoxic NMDA receptor
antagonist. The nontoxic NMDA receptor antagonist may also be
applied to the exterior surface of the extended release carrier and
is thus available for immediate release. Alternatively, the GABA
analog may be contained in a normal release carrier having a
coating that controls the release of the drug. In such a case, the
coating may contain the nontoxic NMDA receptor antagonist, which is
available for immediate release. Where at least one other drug for
treating a CNS disorder or one other therapeutically effective
amount of at least one other pharmacologically active substance is
included in the analgesic composition in addition to the GABA
analog and at least one nontoxic NMDA receptor antagonist, the
other drug may be included in either the extended release carrier,
the immediate release carrier, or both, depending upon the
pharmacologically active substance and its desired effect(s).
[0109] Suitable base materials for controlled release carriers
include combinations of higher aliphatic alcohols and acrylic
resins. Base compositions prepared from such higher aliphatic
alcohols and acrylic resins provide sustained release of
therapeutically active ingredients over a period of time from five
hours and for as much as 24 hours after administration, generally
oral administration, in humans or animals.
[0110] These bases can be prepared from any pharmaceutically
acceptable higher aliphatic alcohol, the most preferred being fatty
alcohols of 10-18 carbon atoms, particularly stearyl alcohol, cetyl
alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol and
mixtures thereof.
[0111] Any acrylic polymer which is pharmaceutically acceptable can
be used for the purposes of the present invention. The acrylic
polymers may be cationic, anionic or non-ionic polymers and may be
acrylates or methacrylates, formed of methacrylic acid or
methacrylic acid esters. These polymers can be synthesized, as
indicated above, to be cationic, anionic or non-ionic, which then
renders the polymers pH dependent and consequently soluble in, or
resistant to, solutions over a wide range in pH.
[0112] In addition, suitable materials for inclusion in a
controlled release carrier include:
[0113] (a) Hydrophilic polymers, such as gums, cellulose ethers,
acrylic resins and protein derived materials. Of these polymers,
the cellulose ethers, especially hydroxyalkylcelluloses and
carboxyalkylcelluloses, are preferred. The analgesic composition
may contain between 1% and 80% (by weight) of at least one
hydrophilic or hydrophobic polymer.
[0114] (b) Digestible, long chain (C.sub.8-C.sub.50, especially
C.sub.12-C.sub.40), substituted or unsubstituted hydrocarbons, such
as fatty acids, fatty alcohols, glyceryl esters of fatty acids,
mineral and vegetable oils, and waxes. Hydrocarbons having a
melting point of between 25.degree. and 90.degree. C. are
preferred. Of these long chain hydrocarbon materials, fatty
(aliphatic) alcohols are preferred. The oral dosage form may
contain up to 60% (by weight) of at least one digestible, long
chain hydrocarbon.
[0115] (c) Polyalkylene glycols. The oral dosage form may contain
up to 60% (by weight) of at least one polyalkylene glycol.
[0116] One particularly suitable carrier comprises at least one
water soluble hydroxyalkyl cellulose, at least one
C.sub.12-C.sub.36, preferably C.sub.14-C.sub.22, aliphatic alcohol
and, optionally, at least one polyalkylene glycol.
[0117] The at least one hydroxyalkyl cellulose is preferably a
hydroxy (C.sub.1 to C.sub.6) alkyl cellulose, such as
hydroxypropylcellulose, hydroxypropylmethylcellulose and,
especially, hydroxyethyl cellulose. The amount of the at least one
hydroxyalkyl cellulose in the present pharmaceutical composition
will be determined, inter alia, by the precise rate of drug release
required. Preferably however, the oral dosage form contains between
1% and 45%, especially between 5% and 25% (by weight) of the at
least one hydroxyalkyl cellulose.
[0118] While the at least one aliphatic alcohol may be, for
example, lauryl alcohol, myristyl alcohol or stearyl alcohol, in
particularly preferred embodiments the at least one aliphatic
alcohol is cetyl alcohol or cetostearyl alcohol. The amount of the
at least one aliphatic alcohol in the present dosage form will be
determined, as above, by the precise rate of drug release required.
It will also depend on whether at least one polyalkylene glycol is
present in or absent from the dosage form. In the absence of at
least one polyalkylene glycol, the dosage form preferably contains
between 20% and 50% (by weight) of the at least one aliphatic
alcohol. When at least one polyalkylene glycol is present in the
dosage form, then the combined weight of the at least one aliphatic
alcohol and the at least one polyalkylene glycol preferably
constitutes between 20% and 50% (by weight) of the total
dosage.
[0119] In the present preferred dosage form, the ratio of, e.g.,
the at least one hydroxyalkyl cellulose or acrylic resin to the at
least one aliphatic alcohol/polyalkylene glycol determines, to a
considerable extent, the release rate of the drug from the
formulation. A ratio of the at least one hydroxyalkyl cellulose to
the at least one aliphatic alcohol/polyalkylene glycol of between
1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being
particularly preferred.
[0120] The at least one polyalkylene glycol may be, for example,
polypropylene glycol or polyethylene glycol, which is preferred.
The number average molecular weight of the at least one
polyalkylene glycol is preferred between 1000 and 15000, more
preferably between 1500 and 12000.
[0121] Another suitable controlled release carrier comprises an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0122] In addition to the above ingredients, a controlled release
carrier may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0123] As an alternative to a controlled release carrier, the
pharmaceutical composition may be in a normal release carrier
having a coating that controls the release of the composition. In
particularly preferred embodiments of this aspect of the invention,
the present dosage form comprises film coated spheroids containing
the pharmaceutical composition and a non-water soluble spheronising
agent. The term spheroid is known in the pharmaceutical art and
means a spherical granule having a diameter of between 0.5 mm and
2.5 mm especially between 0.5 mm and 2.0 mm.
[0124] The spheronising agent may be any pharmaceutically
acceptable material that, together with the active ingredient, can
be spheronised to form spheroids. Microcrystalline cellulose is
preferred. According to a preferred aspect of the present
invention, the film coated spheroids contain between 70% and 99%
(by weight), especially between 80% and 95% (by weight), of the
spheronising agent, especially microcrystalline cellulose.
[0125] In addition to the active ingredient(s) and spheronising
agent, the spheroids may also contain a binder. Suitable binders,
such as low viscosity, water soluble polymers, are well known to
those skilled in the pharmaceutical art. However, water soluble
hydroxy lower alkyl celluloses, such as hydroxy propyl cellulose,
are preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethyl cellulose.
[0126] The spheroids are preferably film coated with a material
that permits release of the pharmaceutical composition at a
controlled rate in an aqueous medium. The film coat is chosen so as
to achieve, in combination with the other ingredients, a desirable
in vitro release rate, preferably between about 12.5% and about
42.5% (by weight) release after 1 hour.
[0127] The film coat will generally include a water insoluble
material such as: (a) a wax, either alone or in admixture with a
fatty alcohol; (b) shellac or zein; (c) a water insoluble
cellulose, especially ethyl cellulose; (d) a polymethacrylate.
[0128] Preferably, the film coat comprises a mixture of the water
insoluble material and a water soluble material. The ratio of water
insoluble to water soluble material is determined by, among other
factors, the release rate required and the solubility
characteristics of the materials selected.
[0129] The water soluble material may be, for example,
polyvinylpyrrolidone or, more preferably, a water soluble
cellulose, especially hydroxypropylmethyl cellulose.
[0130] Suitable combinations of water insoluble and water soluble
materials for the film coat include shellac and
polyvinylpyrrolidone or, more preferably, ethyl cellulose and
hydroxypropylmethyl cellulose. The nontoxic NMDA receptor
antagonist may be applied to the exterior surface of, or included
within, the film coat to provide for the immediate release of the
nontoxic NMDA receptor antagonist while at the same time providing
for the extended release of the GABA analog from the spheroid.
[0131] In another embodiment, in order to obtain a sustained
release of the pharmaceutical composition sufficient to provide a
CNS disorder-treating effect for an extended duration, the
substrate comprising the pharmaceutical composition may be coated
with a sufficient amount of hydrophobic material to obtain a weight
gain level from about 2 to about 30 percent, although the overcoat
may be greater depending upon the physical properties of the
particular pharmaceutical composition and the desired release rate,
among other things. In such a case, the GABA analog may be
contained in the substrate and the nontoxic NMDA receptor
antagonist may be applied to the exterior surface of, or included
within, the hydrophobic coating to provide for the immediate
release of the nontoxic NMDA receptor antagonist while at the same
time providing for the extended release of the GABA analog.
[0132] The solvent which is used for the hydrophobic material may
be any pharmaceutically acceptable solvent, including water,
methanol, ethanol, methylene chloride and mixtures thereof. It is
preferable however, that the coatings be based upon aqueous
dispersions of the hydrophobic material.
[0133] In certain preferred embodiments of the present invention,
the hydrophobic polymer comprising the sustained-release coating is
a pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers,
methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl
methacrylate copolymer, polyacrylic acid, polymethacrylic acid,
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
methyl methacrylate, polymethacrylate, poly(methyl methacrylate)
copolymer, polyacrylamide, poly(methacrylic acid anhydride), and
glycidyl methacrylate copolymers.
[0134] In other preferred embodiments, the hydrophobic polymer
which may be used for coating the substrates of the present
invention is a hydrophobic cellulosic material such as
ethylcellulose. Those skilled in the art will appreciate that other
cellulosic polymers, including other alkyl cellulosic polymers, may
be substituted for part or all of the ethylcellulose included in
the hydrophobic polymer coatings of the present invention.
[0135] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic polymer, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic polymer will further improve the physical
properties of the film. For example, because ethylcellulose has a
relatively high glass transition temperature and does not form
flexible films under normal coating conditions, it is necessary to
plasticize the ethylcellulose before using the same as a coating
material. Generally, the amount of plasticizer included in a
coating solution is based on the concentration of the film-former,
e.g., most often from about 1 to about 50 percent by weight of the
film-former. Concentration of the plasticizer, however, can only be
properly determined after careful experimentation with the
particular coating solution and method of application.
[0136] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is especially preferred.
[0137] Examples of suitable plasticizers for the acrylic polymers
of the present invention include citric acid esters such as
triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and
possibly 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, and triacetin, although it is possible
that other water-insoluble plasticizers (such as acetylated
monoglycerides, phthalate esters, castor oil, etc.) may be used.
Triethyl citrate is especially preferred.
[0138] Sustained-release spheroids or beads, coated with a
therapeutically active agent, i.e., pharmaceutical composition, are
prepared, e.g., by dissolving the pharmaceutical composition in
water and then spraying the solution onto a substrate using a
Wurster insert. Optionally, additional ingredients are also added
prior to coating the beads in order to assist the pharmaceutical
composition binding to the substrates, and/or to color the
solution, etc. For example, a product which includes hydroxypropyl
methylcellulose, with or without colorant, may be added to the
solution and the solution mixed (e.g., for about 1 hour) prior to
application of the same onto the beads. The resultant coated
substrate, in this example beads, may then be optionally overcoated
with a barrier agent, to separate the pharmaceutical composition
from the hydrophobic sustained-release coating. An example of a
suitable barrier agent is one which comprises hydroxypropyl
methylcellulose. However, any film-former known in the art may be
used. It is preferred that the barrier agent does not affect the
dissolution rate of the final product.
[0139] The plasticized aqueous dispersion of hydrophobic polymer
may be applied onto the substrate comprising the pharmaceutical
composition by spraying using any suitable spray equipment known in
the art. In a preferred method, a Wurster fluidized-bed system is
used in which an air jet, injected from underneath, fluidizes the
core material and effects drying while the acrylic polymer coating
is sprayed thereon. A sufficient amount of the aqueous dispersion
of hydrophobic polymer to obtain a predetermined sustained-release
of said pharmaceutical composition when said coated substrate is
exposed to aqueous solutions, e.g. gastric fluid, is preferably
applied, taking into account the physical characteristics of the
pharmaceutical composition, the manner of incorporation of the
plasticizer, etc. After coating with the hydrophobic polymer, a
further overcoat of a film-former is optionally applied to the
beads. This overcoat is provided, if at all, in order to
substantially reduce agglomeration of the beads.
[0140] Next, the coated beads are cured in order to obtain a
stabilized release rate of the pharmaceutical composition.
[0141] The sustained-release profile of the formulations of the
invention can be altered, for example, by varying the thickness of
the hydrophobic coating, changing the particular hydrophobic
material used, or altering the relative amounts of, e.g., different
acrylic resin lacquers, altering the manner in which the
plasticizer is added (e.g., when the sustained-release coating is
derived from an aqueous dispersion of hydrophobic polymer), by
varying the amount of plasticizer relative to hydrophobic polymer,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, etc. As noted above, the
nontoxic NMDA receptor antagonist may be applied to the exterior
of, or contained within, any coating of a carrier containing a GABA
analog to provide for the immediate release of the nontoxic NMDA
receptor antagonist while at the same time providing for the
extended release of the GABA analog.
[0142] The coating solutions of the present invention may contain,
in addition to the film-former, plasticizer, and solvent system
(i.e., water), a colorant to provide elegance and product
distinction. Color may be added to the solution of the
pharmaceutical composition instead, or in addition to the aqueous
dispersion of hydrophobic polymer.
[0143] In another embodiment, the pharmaceutical composition of the
present invention is in an aqueous suspension. Aqueous suspensions
can include pharmaceutically acceptable excipients such as
suspending agents, e.g., sodium carboxymethyl cellulose,
methylcellulose, hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as naturally occurring phosphatides, e.g.,
lecithin, or condensation products of an alkylene oxide with fatty
acids, e.g., polyoxyethylene stearate, or condensation products of
ethylene oxide with long chain aliphatic alcohols, e.g.,
heptadecaethylene-oxycetanol, or condensation products of ethylene
oxide with partial esters derived from fatty acids and a hexitol,
e.g., polyoxyethylene sorbitol monooleate or condensation products
of ethylene oxide with partial esters derived from fatty acids and
hexitol anhydrides, e.g., polyoxyethylene sorbitan monooleate. The
aqueous suspensions can also contain one or more preservatives,
e.g., ethyl- or n-propyl-p-hydroxy benzoate, one or more coloring
agents, one or more flavoring agents and one or more sweetening
agents, such as sucrose, saccharin or sodium or calcium
cyclamate.
[0144] The pharmaceutical composition herein can be formulated as a
solid, liquid, powder, elixir, injectable solution, etc. When
formulated for oral delivery, the combination of drugs herein may
be in the form of tablets, liquids, troches, lozenges, quick
dissolve tablets, aqueous or oily suspensions, multiparticulate
formulations including dispersible powders, granules, carrier
spheroids or coated inert beads, emulsions, hard or soft capsules,
syrups or elixirs, microparticles (e.g., microcapsules,
microspheres and the like), buccal tablets, etc. The pharmaceutical
preparations can be sterilized and if desired mixed with auxiliary
agents, e.g., lubricants, preservatives, stabilizers, emulsifiers,
salts for influencing osmotic pressure buffers, coloring, flavoring
and/or aromatic substances and the like. They can also be combined
where desired with other active agents, e.g., other analgesic
agents. For oral administration, particularly suitable are tablets,
dragees, liquids, drops, suppositories, capsules, caplets and
gelcaps. The compositions intended for oral use may be prepared
according to any method known in the art. When prepared as tablets,
the tablets may be uncoated or they may be coated by known
techniques for elegance or to further delay release of the active
ingredients. Formulations for oral use may also be presented as
hard gelatin capsules wherein the active ingredient is mixed with
an inert diluent.
[0145] The following examples are illustrative of pharmaceutical
compositions for the treatment of CNS disorders in accordance with
the invention: TABLE-US-00001 Drug Components Dosage GABA Analog,
Nontoxic NMDA Other Drug Example Form mg Receptor Antagonist, mg
Component, mg 1 oral gabapentin, dextromethorphan HBr, -- 50-800
10-750 2 oral gabapentin, d-methadone HCl, -- 50-800 50-800 3 oral
pregabalin, dextromethorphan HBr, -- 10-600 10-500 4 oral
pregabalin, d-methadone HCl, -- 10-600 10-800 5 oral gabapentin,
dextromethorphan HBr, nicotine or nicotinic 50-800 10-500 compound,
5-200 6 oral gabapentin, dextromethorphan HBr, tacrine HCl, 50-800
10-500 5-50 7 oral gabapentin, dextromethorphan HBr, donezepil HCl,
50-800 10-500 5-50 8 oral gabapentin, dextromethorphan HBr,
carbidopa, 10-100, 50-800 10-500 and levodopa, 25-250 9 oral
pregabalin, dextromethorphan HBr, -- 10-600 10-500 10 oral
pregabalin, d-methadone HCl, -- 10-600 10-500 11 injectable
gabapentin, dextromethorphan HBr, -- 10-600 10-500 12 injectable
pregabalin, dextromethorphan HBr, -- 10-600 10-500
[0146] It will be understood that various modifications may be made
to the embodiments disclosed herein. Therefore, the above
description should not be construed as limiting, but merely as
exemplifications of preferred embodiments. For example, NMDA
receptor antagonists other than dextromethorphan can be utilized in
the CNS disorder-treating pharmaceutical composition described
herein. Those skilled in the art will envision other modifications
within the scope and spirit of the claims appended hereto.
* * * * *